Stable Warfarin Dose Research Articles

Pharmacogenomics research and clinical implementation in Brazil.

We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

An Ensemble Model With Clustering Assumption for Warfarin Dose Prediction in Chinese Patients.

The prediction of daily stable warfarin dosage for a specific patient is difficult. To improve the predictive accuracy and to build a highly accurate predictive model, we developed an ensemble learning method, called evolutionary fuzzy c-mean (EFCM) clustering algorithm with support vector regression (SVR). A dataset of 517 Han Chinese patients was collected from the data of The First Affiliated Hospital of Soochow University and dataset of International Warfarin Pharmacogenetics Consortium for training and testing. In EFCM+SVR, we adopted SVR to build a generalized base model (SVR model). To achieve an accurate prediction on patients with large dosage, we proposed an EFCM clustering algorithm that can be used to cluster the training set and designed a clustering model on clusters and centroids. The SVR and clustering models were integrated into an ensemble model by stepwise functions. In the experiment, three artificial neural networks, SVR, two ensemble models, and three regression models were used as comparators to the EFCM+SVR model, which obtained the smallest mean absolute error (0.67 mg/d) in warfarin dose prediction and the largest R-squared (43.9%). The model achieved satisfactory prediction in terms of the percentage of patients whose predicted dose of warfarin was within 15% and 20% of the actual stable therapeutic dose (15%-p of 36% and 20%-p of 46.6%).

Genotype-guided dosing versus conventional dosing of warfarin: A meta-analysis of 15 randomized controlled trials.

Genotype-guided warfarin dosing algorithm is designed to predict the initial and stable dose of warfarin. However, whether this strategy is superior to conventional dosing method has not been consistently proven. To determine the benefit of genotype-guided dosing vs conventional dosing of warfarin, we performed a meta-analysis. Literature was searched in PubMed, Embase and Central for published studies, and in clinicaltrials.gov for unpublished studies. Randomized controlled trials (RCTs) comparing genotype-guided dosing with conventional dosing of warfarin were included in the meta-analysis. Risk of bias of eligible RCTs was assessed with the Cochrane Collaboration's tool. Meta-analysis was conducted by STATA software. The reliability of currently available evidence was determined with TSA software. Fifteen RCTs with a total of 4852 patients were identified for the meta-analysis. Genotype-guided dosing of warfarin was associated with higher percentage time within therapeutic range (PTTR) and more patients achieving stable dose at >1month follow-up, shorter time to first therapeutic international normalized ratio (INR), shorter time to stable therapeutic dose, and decreased risk of warfarin-related major bleeding events compared with conventional dosing. However, there were no statistically significant differences in PTTR and incidence of patients achieving stable dose within 1month, INR >4, all bleeding events, thromboembolism and all-cause mortality. Genotype-guided dosing should be considered in patients initiating warfarin treatment, especially in those with a history of haemorrhage. However, further studies are still needed to determine the cost-effectiveness of routine warfarin-related genotypes testing.

Anticoagulation management by physician-clinical pharmacist team for patients with valvular atrial fibrillation

Objective To evaluate the effectiveness of anticoagulation management by physician-clinical pharmacist team for patients with valvular atrial fibrillation. Methods One hundred and seventy two patients with valvular atrial fibrillation received warfarin therapy for anticoagulation during hospitalization in Linyi People′s Hospital from January 2014 to December 2016, the patients continued to receive warfarin therapy for>6 months after discharge. The patients were randomly assigned in two groups: the anticoagulation management was given by physician-clinical pharmacist team in 87 cases (trial group), while the dosage of wargarin was adjusted in outpatient department by physicians alone in 85 cases (control group). The goal attainment rate of international normalized ratio (INR), the proportion of patients with a stable warfarin dose, knowledge of anticoagulants, belief of medication, medication compliance were compared between two groups. Results There were no significant differences in age, sex, body weight, smoking and drinking habits, valvular disease type, comorbidities; and the initial INR, knowledge of anticoagulants, belief of medication and medication compliance at admission between two groups (all P>0.05). The goal attainment rate of INR (52.17% vs. 41.02%, χ2=8.178,P=0.004), the proportion of patients with a stable dose of warfarin (74.71% vs. 56.47%, χ2=6.349, P=0.012), the knowledge of anticoagulants(11.03±2.25 vs. 10.08±1.86, t=3.018, P=0.003), the belief of medication[(12.23±2.07) vs.(11.67±1.48), t=2.042, P=0.043], and the medication compliance[(7.36±0.89) vs. (7.04±1.10), t=2.112 8, P=0.036] in the trial group were significantly higher than those in control group. Conclusion Anticoagulation management by physician-clinical pharmacist team can improve the management level of anticoagulation and the knowledge of anticoagulans, enhance the medication belief, improve the goal attainment rate of INR and the compliance rate of medication in patients with valvular atrial fibrillation. Key words: Atrial fibrillation; Warfarin; Anticoagulation management service; Physician; Clinical pharmacist; International normalized ratio

Feasibility and safety of a 12-week INR follow-up protocol over 2years in an anticoagulation clinic: a single-arm prospective cohort study.

The 2012 American College of Chest Physicians' guidelines recommended a 12-week INR follow-up interval may be appropriate for patients on stable warfarin doses. Limited evidence supports this recommendation. A single-arm, prospective cohort studyover 24months was completed in a Veterans Affairs anticoagulation clinicto determine the long-term feasibility and safety of implementing an extended INR follow-up interval in Veterans on stable doses of warfarin. Participants were required to have a stable warfarin dose for 6months prior to enrollment. A prespecified protocol was used to titrate, extend, and manage the INR interval up to 12weeks. Scheduling of extended INR intervals was a primary outcome. Safety outcomes included major and serious bleeding and thromboembolic events. A post-hoc comparison of baseline characteristics between individuals who were scheduled for at least 4 consecutive 12-week INR follow-up intervals and those who were not was completed. Of the 50 participants, 36 (72%) were scheduled for at least one 12-week interval and 15 (30%) were scheduled for 4 consecutive intervals. There were 2 thromboembolic events that occurred in 1 participant. There were 28 major and serious bleeding events in 19 participants; 8 occurred while on the extended INR interval. In the post-hoc analysis, no participants scheduled for 4 consecutive 12-week intervals had heart failure. Based on 2years of monitoring, a 12-week INR follow-up interval using a detailed protocol with titration of INR interval extension appears feasible for a subset of patients. Patients with heart failure may not be suitable for this intervention.

Pharmaceutical Care Increases Time in Therapeutic Range of Patients With Poor Quality of Anticoagulation With Warfarin.

Thromboembolic events are associated with high mortality and morbidity indexes. In this context, warfarin is the most widely prescribed oral anticoagulant agent for preventing and treating these events. This medication has a narrow therapeutic range and, consequently, patients usually have difficulty in achieving and maintaining stable target therapeutics. Some studies on the literature about oral anticoagulant management showed that pharmacists could improve the efficiency of anticoagulant therapy. However, the majority of these studies included general patients retrospectively. The aim of this study was to prospectively evaluate a pharmacist’s warfarin management in patients with poor quality of anticoagulation therapy (Time in the Therapeutic Range- TTR < 50%). We included 268 patients with atrial fibrillation (AF) and without stable dose of warfarin (TTR < 50%, based on the last three values of International Normalized Ratio-INR). We followed them up for 12 weeks, INR values were evaluated and, when necessary, the dose adjustments were performed. During the first four visits, patient’s INR was measured every 7 days. Then, if INR was within the target therapeutic range (INR: 2–3), the patient was asked to return in 30 days. However, if INR was out the therapeutic target, the patient was asked to return in 7 days. Adherence evaluation was measured through questionnaires and by counting the pills taken. Comparison between basal TTR (which was calculated based on the three last INR values before prospective phase) and TTR of 4 weeks (calculated by considering the INR tests from visits 0 to 4, in the prospective phase of the study) and basal TTR and TTR of 12 weeks (calculated based on the INR tests from visits 0 to 12, in the prospective phase of the study) revealed significant statistical differences (0.144 ± 0.010 vs. 0.382 ± 0.016; and 0.144 ± 0.010 vs. 0.543 ± 0.014, p < 0.001, respectively). We also observed that the mean TTR of 1 year before (retrospective phase) was lower than TTR value after 12 weeks of pharmacist-driven treatment (prospective phase) (0.320 ± 0.015; 0.540 ± 0.015, p < 0.001). In conclusion, pharmaceutical care was able to improve TTR values in patients with AF and poor quality of anticoagulation with warfarin.

Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial

Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy. In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, and diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided pharmacogenetics guided (PHG), and where it was adjusted according to the clinical parameters non pharmacogenetics guided (NPHG). Genotyping of CYP2C9*2, *3, and VKORC1 was performed using the real-time polymerase chain reaction method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0-3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0-3.0) range in at least 2 consecutive measurements. In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group [mean = 26% (SD 25.0)] than in the NPHG group [mean = 14% (SD 18.6)], [Δ = 12; 95% confidence interval, 0-23; P = 0.040]. There was no significant difference in other 2 indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%) than in the NPHG group 7/32 (22%) (odds ratio = 3.13, 95% confidence interval, 0.92-10.98; P = 0.039). CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with AF. There is no evidence for such conclusion in patients with DVT and PE.

Evaluation of SAMe-TT2R2 Score on Predicting Success With Extended-Interval Warfarin Monitoring

In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TT2R2 score (considering sex, age, medical history, treatment, tobacco, and race) predicts anticoagulation control during standard follow-up (every 4 weeks), with lower scores associated with greater time in therapeutic range. To evaluate the ability of the SAMe-TT2R2 score in predicting success with extended-interval warfarin follow-up in patients with previously stable warfarin doses. In this post hoc analysis of a single-arm feasibility study, baseline SAMe-TT2R2 scores were calculated for patients with ≥1 extended-interval follow-up visit. The primary analysis assessed achieved weeks of extended-interval follow-up according to baseline SAMe-TT2R2 scores. A total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT2R2 score was 1 (range 0-5). Lower SAMe-TT2R2 scores appeared to be associated with greater duration of extended-interval follow-up achieved, though the differences between scores were not statistically significant. No individual variable of the SAMe-TT2R2 score was associated with achieved weeks of extended-interval follow-up. Analysis of additional patient factors found that longer duration (≥24 weeks) of prior stable treatment was significantly associated with greater weeks of extended-interval follow-up completed ( P = 0.04). Conclusion and Relevance: This pilot study provides limited evidence that the SAMe-TT2R2 score predicts success with extended-interval warfarin follow-up but requires confirmation in a larger study. Further research is also necessary to establish additional predictors of successful extended-interval warfarin follow-up.

The Influence of CYP4F2 Polymorphisms on Warfarin Doses in Korean Patients with a Variety of Diseases

Purpose We sought to determine if the CYP4F2 gene could affect warfarin maintenance dosage in Korean patients with a variety of diseases. CYP4F2 was reported to affect warfarin dose, but it was controversial. Some papers showed that CYP4F2 genotype could affect warfarin stable dose to some extent. But other papers reported that CYP4F2 genotype did not affect warfarin dose. Methods We enrolled 101 patients treated with warfarin in our registry. Non-genetic factors (clinical characteristics, stable warfarin dose, INR, medication information) and CYP4F2 polymorphisms were assessed. The definition of warfarin stable dose was the amount of medication given to maintain the patient’s INR within the target range throughout at least 3 consecutive laboratory measurements separated by at least 1 week. Each patient’s target therapeutic INR range was determined by the clinicians according to the indication for warfarin treatment. Results In our study, average patient age was 64.0± 11.9 years. Females accounted for 52% of the sample. The average warfarin maintenance dose was 3.26± 1.38 (1-9) mg/day. Compared with CYP4F2 wild type patients (GG), the patients carrying a CYP4F2 heterozygous variant (GA) or a CYP4F2 homozygous variant (AA) required higher warfarin dose. The mean warfarin dose in the patients with the CYP4F2 AA genotype was 4.1± 1.9 mg/day, while that for the patients with the CYP4F2 GA genotype was 3.3± 1.3 mg/day, and that for the patients with the CYP4F2 GG genotype was 3.0± 1.2 mg/day. The difference among them was significant (P= 0.038). Conclusion CYP4F2 polymorphisms statistically influenced the stability of warfarin maintenance dosage in Korean patients with a variety of diseases. Keywords: CYP4F2 polymorphisms, Warfarin dose, Korean

Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.

The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

Impact of VKORC1, CYP4F2 and NQO1 gene variants on warfarin dose requirement in Han Chinese patients with catheter ablation for atrial fibrillation

BackgroundThe anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation.MethodsA total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study. The study population included had high (≥2) risk according to the CHA2DS2-VASc risk score. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 were analyzed by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Multiple linear regression analysis was applied to depict the impact of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 on the daily stable warfarin dose requirement.ResultsCarriers of VKORC1 rs9923231 AG/GG genotypes required significantly higher warfarin dose (3.03 ± 0.28 mg/day, 7.19 mg/day, respectively) than AA carriers (2.52 ± 0.07 mg/day; P < 0.001). Carriers of CYP4F2 rs2108622 CT/TT genotypes required significantly higher warfarin dose (3.38 ± 0.22 mg/day, 2.79 ± 0.19 mg/day, respectively) than CC carriers (2.41 ± 0.08 mg/day; P < 0.001). However, the warfarin dose for carriers of NQO1 rs1800566 CT/TT genotypes (2.46 ± 0.24 mg/day, 3.01 ± 0.27 mg/day, respectively) was not significantly higher than that for the CC carriers (2.33 ± 0.1 mg/day). The multiple linear regression model including genotypes and demographic characteristics, could explain 20.1% of individual variations in the daily stable warfarin dose in Sichuan Han Chinese. VKORC1 rs9923231 contributed most (15%) to the individual variations in daily stable warfarin dose, while CYP4F2 rs2108622 contributed least (3%).ConclusionNQO1 rs1800566 is not a significant genetic factor of warfarin dose for Han Chinese, whereas VKORC1 rs9923231 and CYP4F2 rs2108622 are significant genetic factors, which could explain 15% and approximately 3% of individual variations in the daily stable warfarin dose respectively.

The influence of fibrate initiation on INR and warfarin dose in patients receiving chronic warfarin therapy.

Several drug interaction compendia report a risk of warfarin potentiation after initiation of a fibrate; however, the evidence of this interaction is limited. The objective of this study was to evaluate warfarin dose and international normalized ratio (INR) response among a large sample of patients receiving chronic warfarin who initiated a fibrate. This was a retrospective, one-sample, pre-to-post study. Adult patients who were receiving chronic warfarin therapy at the time of gemfibrozil or fenofibrate dispensing between 1/1/2000 and 3/31/2016 were included. Patients had at least one and two therapeutic INRs during the 90 days prior to (baseline) and after (follow-up), respectively, fibrate initiation. Comparison of stable warfarin dose:INR ratio between the baseline and follow-up periods and assessment of safety outcomes during follow-up were performed. There were 321 patients included. Patients were predominantly male (62.6%) with an indication of atrial fibrillation (44.2%). The mean warfarin dose:INR ratio was equivalent between the baseline and follow-up periods (13.4mg/INR [± 6.9] vs. 13.5mg/INR [± 7.5], respectively, p = 0.711). Rates of thromboembolism, bleeding, and all-cause mortality in the 90-day follow up were 0, 0.6, and 1.2%, respectively. Although individual patients may have labile INRs after fibrate initiation, no significant interaction between fibrate and warfarin in a large sample of real world patients was identified. The utility of additional INR monitoring after fibrate initiation in otherwise stable patients receiving chronic warfarin therapy is unclear.

A prediction study of warfarin individual stable dose after mechanical heart valve replacement: adaptive neural-fuzzy inference system prediction

BackgroundIt’s difficult but urgent to achieve the individualized rational medication of the warfarin, we aim to predict the individualized warfarin stable dose though the artificial intelligent Adaptive neural-fuzzy inference system (ANFIS).MethodsOur retrospective analysis based on a clinical database, involving 21,863 patients from 15 Chinese provinces who receive oral warfarin after the heart valve replacement. They were allocated into four groups: the external validation group (A group), the internal validation group (B group), training group (C group) and stratified training group (D group). We used a univariate analysis of general linear models(GLM-univariate) to select the input variables and construct two prediction models by the ANFIS with the training and stratified training group, and then verify models with two validation groups by the mean squared error(MSE), mean absolute error(MAE) and the ideal predicted percentage.ResultsA total of 13,639 eligible patients were selected, including 1639 in A group, 3000 in B group, 9000 in C group, and 3192 in D group. Nine input variables were selected out and two five-layered ANFIS models were built. ANFIS model achieved the highest total ideal predicted percentage 63.7%. In the dose subgroups, all the models performed best in the intermediate-dose group with the ideal predicted percentage 82.4~ 86.4%, and the use of the stratified training group slightly increased the prediction accuracy in low-dose group by 8.8 and 5.2%, respectively.ConclusionAs a preliminary attempt, ANFIS model predicted the warfarin stable dose properly after heart valve surgery among Chinese, and also proved that Chinese need lower anticoagulation intensity INR (1.5–2.5) to warfarin by reference to the recommended INR (2.5–3.5) in the developed countries.

Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Aim:To evaluate applicability of CYP2C9*2, *3 and VKORC1–1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients.Patients & methods:Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD.Results:Frequency of CYP2C9*2, *3 and VKORC1–1639G > A alleles is 13.6, 0.0 and 46.5% respectively. The international warfarin pharmacogenetics consortium algorithm was more reliable (MAE = 8.9 ± 1.4; R2 = 0.350) than both the clinical algorithm (MAE = 10.4 ± 1.4; R2 = 0.128;) and the fixed-dose algorithm (MAE = 11.1 ± 1.7).Conclusion:The international warfarin pharmacogenetics consortium algorithm can be reliably applied for predicting the WSD in Palestinian population.

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses.

Effects of VKORC1 and CYP2C9 gene polymorphisms on the stable dosage of warfarin and anticoagulation in patients with hypertrophic cardiomyopathy complicated with atrial fibrillation

Objective To investigate the gene polymorphisms and clinical features of vitamin K epoxide reductase complex 1(VKORC1) and cytochrome P450 2C9(CYP2C9), and their correlation with stable dosage of warfarin, the risk of hemorrhage and over anticoagulation for patients with hypertrophic cardiomyopathy. Methods A retrospective study was performed on 60 patients with hypertrophic cardiomyopathy(HCM) combined with atrial fibrillation(AF) who were admitted and regularly took oral warfarin as anticoagulation from January 2011 to December 2016.The clinical data such as age, body height, body weight, stable warfarin dosage and the situation of hemorrhage and over anticoagulation were recorded.Genotypes of CYP2C9 and VKORC1 were detected with fluorescence PCR-capillary electrophoresis sequencing and the relationship between the genotype and clinical features and the stable dose of warfarin, hemorrhage and over anticoagulation were analyzed by statistical methods. Results Among the 60 patients, VKORC1-1639G>A detection showed that 50 patients were AA type, 9 patients were AG type, 1 patient was GG type, the stabledosage of AA type patients were significant lower than that of AG type patients(P 0.05); CYP2C9 detection showed that 51 patients were *1/*1 type, 6 patients were *1/*3 type, 3 patients were *3/*3 type, *2 allele was not found, the stable dosage of patients who carry the *3 mutation were significant lower than that of *1/*1 type patients, and the more *3 mutation they own, the lower dosage they require(P 0.05). The incidence of hemorrhage and anticoagulation was significantly higher in patients aged 65 years or older than those who were younger than 65 years(P<0.05). Conclusion Stable warfarin dosage has relationship with different genotypes of VKORC1 and CYP2C9 in HCM patients, age may be a factor of warfarin over anticoagulation and hemorrhage. Key words: Hypertrophic cardiomyopathy; Atrial fibrillation; Warfarin; Vitamin K epoxide reductase complex 1; cytochrome P450 2C9; Gene polymorphisms; Hemorrhage; Over anticoagulation

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response

Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, CYP2C9∗2 rs1799853, CYP2C9∗3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5–0.7% with an improvement in dose prediction accuracy of ∼1–2%. Although there is complex regulation across the CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.

The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients

PurposeThe aim of this study was to investigate the contributions of non-genetic and genetic factors on the variability of stable warfarin doses in Thai patients.MethodsA total of 250 Thai patients with stable warfarin doses were enrolled in the study. Demographics and clinical data, e.g., age, body mass index, indications for warfarin and concomitant medications, were documented. Four single nucleotide polymorphisms in the VKORC1 − 1639G > A, CYP2C9*3, CYP4F2 rs2108622, and UGT1A1 rs887829 genes were detected from gDNA using TaqMan allelic discrimination assays.ResultsThe patients with variant genotypes of VKORC1 − 1639G > A required significantly lower warfarin stable weekly doses (SWDs) than those with wild-type genotype (p < 0.001). Similarly, the patients with CYP2C9*3 variant allele required significantly lower warfarin SWDs than those with homozygous wild-type (p = 0.006). In contrast, there were no significant differences in the SWDs between the patients who carried variant alleles of CYP4F2 rs2108622 and UGT1A1 rs887829 as compared to wild-type allele carriers. Multivariate analysis, however, showed that CYP4F2 rs2108622 TT genotype accounted for a modest part of warfarin dose variability (1.2%). In contrast, VKORC1 − 1639G > A, CYP2C9*3, CYP4F2 rs2108622 genotypes and non-genetic factors accounted for 51.3% of dose variability.ConclusionsVKORC1 − 1639G > A, CYP2C9*3, and CYP4F2 rs2108622 polymorphisms together with age, body mass index, antiplatelet drug use, amiodarone use, and current smoker status explained 51.3% of individual variability in stable warfarin doses. In contrast, the UGT1A1 rs887829 polymorphism did not contribute to dose variability.

The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement.

Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patientswith mechanical heart valve replacement (MHVR). A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD. The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (P<.05). But they were ruled out in the multivariate regression analysis. There were no significant differences in the average warfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05). The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (P<.05), but their contributions were not significant after accounting for other factors. MIR133B rs142410335 makes no significant contributions to warfarin stable dosage in Han Chinese patientswith MHVR neither in univariate regression nor in multivariate regression analyses.